ASH 2010 for physicians
ASH 2010 Summary of Multiple Myeloma
Presentations for Physicians
Introduction
The 52nd Annual Society of Hematology (ASH) Annual Meeting was held December 4th
through 7th, 2010, in Orlando, Florida. This report summarizes presentations at the 2010 ASH
Annual Meeting, organized by topics rather than by sessions, providing an overview of
information on new drugs in development; clinical trial results; treatment by patient
characteristics, e.g., transplant eligibility or stage of disease; risk stratification and staging;
disease biology including bone disease and use of bisphosphonates; and maintenance therapy.
Although maintenance therapy is summarized in its own section, some trials that include
maintenance therapy are summarized in more relevant sections, as many trials are now including
some kind of continuing treatment for at least some patients.
On December 3, the International Myeloma Foundation (IMF) and the Postgraduate Institute for
Medicine sponsored a symposium that presented an overview of the most recent data from
clinical trials to allow participants to provide better care for their patients with multiple
myeloma. Dr. Brian G.M. Durie introduced the presenters and topics at the symposium.
Summaries of these presentations are included under the appropriate headings.
Multiple myeloma was the topic of many presentations at ASH, including the following:
Education sessions were held on advances in the basic science of plasma cell disorders and
on supportive care in plasma cell dyscrasias.
An education session on high risk hematologic diseases included a talk on ultra high-risk
myeloma.
A scientific session was conducted on therapeutic targeting of the myeloma stem cell.
Over a dozen simultaneous oral sessions (comprising about 6 presentations each) were held
specifically on myeloma, with many other sessions presenting related information on
transplantation, venous thromboembolism, stem cell collection, tumor cell biology, and other
topics of interest.
Three poster sessions featured hundreds of posters about myeloma and related topics, e.g.,
transplantation, pharmacoeconomics, and new drugs in development.
New Drugs in Development
Studies of new drugs in development discussed in this report include:
Carfilzomib (PX-171), a proteasome inhibitor
Pomalidomide, an immunomodulatory drug
Elotuzumab, a monoclonal antibody
Temsirolimus, an inhibitor of the mammalian target of rapamycin
PD0332991, an inhibitor of cyclin-dependent kinases
1

---

ASH 2010 for physicians
IMF Symposium: Case Study 5: Novel Agents and Regimens was presented by Robert Z.
Orlowski, MD, PhD, The University of Texas M. D. Anderson Cancer Center, Houston, TX.
Most of the symposium participants agreed that relapsed/refractory myeloma could be defined as
progressive disease on or within 60 days of the last treatment. The National Comprehensive
Cancer Network (NCCN) practice guidelines for multiple myeloma recommend repeating the
primary therapy if relapse occurs at greater than 6 months; there is the most evidence for using
bortezomib, bortezomib plus pegylated liposomal doxorubicin (PLD), or lenalidomide plus
dexamethasone; other possibilities include bendamustine, bortezomib plus dexamethasone,
lenalidomide, high-dose cyclophosphamide alone or with VAD, thalidomide alone or with
dexamethasone, dexamethasone alone, DCEP, or DT-PACE. Dr. Orlowski commented that he
would prefer to repeat the primary therapy if relapse occurs at 12 months or more. Upcoming
promising approaches include the novel single agents carfilzomib and pomalidomide, which are
discussed below. New combinations that seem promising that are in trial include bortezomib and
lenalidomide in combination with histone deacetylase (HDAC) inhibitors, monoclonal
antibodies, proteasome inhibitors, and other agents. It is also possible to add old agents that are
new again to prior active regimens, e.g., cyclophosphamide. Agents that have been used
previously can be used again in different combinations.
Carfilzomib (PX-171): a Proteasome Inhibitor
Two carfilzomib trials are summarized in Table 1.
Carfilzomib, Lenalidomide, and Dexamethasone In Newly Diagnosed Multiple Myeloma:
Initial Results of Phase I/II MMRC Trial (Abstract 862) was presented by Andrzej J.
Jakubowiak, University of Michigan, Ann Arbor, MI.
Results of PX-171-003-A1, An Open-Label, Single-Arm, Phase II (Ph 2) Study of
Carfilzomib (CFZ) In Patients (pts) with Relapsed and Refractory Multiple Myeloma
(MM) (Abstract 985) David Samuel diCapua Siegel, John Theurer Cancer Center, Hackensack
University Medical Center, Hackensack, NJ.
Table 1. Summary of Carfilzomib Studies
Abstract
Patients
Agents and Doses
Side Effects
Responses
First Author
Phase
Follow-up
Abstract 862
newly diagnosed
carfilzomib (C) days
mostly mild; grade 3
stringent complete
A.J. Jakubowiak
patients
1, 2, 8, 9, 15, and 16;
to 4 neutropenia
response
phase I: the
20 to 27 to 38 mg/m2
infrequent, no fevers
(sCR)/CR/near
maximum tolerated
lenalidomide (R):
or decline in
(n)CR=55%
dose (MTD); dose-
continuously on days
neutrophils with
sCR=22%
limiting toxicities
1 to 21; 25 mg per
treatment; no
partial response (PR)
(DLT), n= 31 (27
day
emergence of
or better=96% (100%
evaluable)
low-dose
clinically significant
after 4 cycles)
phase II: to be
dexamethasone (d);
peripheral neuropathy
at least very good
initiated
(CRd) days 1, 8, 15,
(PN)
(VG)PR=83% and
median F/U 6 months
and 22 of a 28 day
CR/nCR=67% after 8
cycles
cycles
CRd every other
week as maintenance
Abstract 985
patients with
carfilzomib first dose
77% of patients had
A1 responses: overall
2

---

ASH 2010 for physicians
D.S. Siegel
progressive disease
20 mg/m2,
pre-existing PN
response rate
(PD) after last
registration cohort
treatment-emergent
(ORR)=24%, at least
therapy with prior
dose was 27 mg/m2
adverse events (AE)
VGPR=5.5% (0.4 %
lines of therapy,
included few grade 3
CR), PR=18.7%,
including bortezomib
to 4 hematologic
minimal response
(100%) and
toxicities:
(MR)=10%
thalidomide or
neutropenia=10%
median progression-
lenalidomide
non-hematologic
free survival
phase II: A1 n=257
toxicities: 12% any
(PFS)=3.7 months
evaluated for
grade PN and 0.8%
median overall
response of the 266
grade 3 and 4 PN;
survival (OS)=15.5
patients enrolled and
most discontinuations
months; median OS
in the safety
due to PD and none
not reached in
population
to emerging PN
responders
95 deaths on study
duration of response
mostly due to
(DOR)=8.3 months in
progressive disease
both PR and MR
(PD); 16% of patients
populations
completed all 12
clinical benefit (at
cycles
least MR)=34%
Pomalidomide: an Immunomodulatory Drug (IMiD)
Four pomalidomide trials are summarized in Table 2.
Pomalidomide Plus Low-Dose Dexamethasone In Myeloma Refractory to Both Bortezomib
and Lenalidomide: Comparison of Two Dosing Strategies In Dual-Refractory Disease
(Abstract 863) was presented by Martha Lacy, MD, Division of Hematology, Department of
Internal Medicine, Mayo Clinic, Rochester, MN.
A Phase I/II Multi-Center, Randomized, Open Label Dose Escalation Study to Determine
the Maximum Tolerated Dose, Safety, and Efficacy of Pomalidomide Alone or In
Combination with Low-Dose Dexamethasone In Patients with Relapsed and Refractory
Multiple Myeloma Who Have Received Prior Treatment That Includes Lenalidomide and
Bortezomib (Abstract 864) was presented by Paul G Richardson, MD, Dana-Farber Cancer
Institute, Boston, MA.
Phase II Study of 2 Modalities of Pomalidomide (CC4047) Plus Low-Dose Dexamethasone
as Therapy for Relapsed Multiple Myeloma. IFM 2009-02 (Abstract 859) was presented by
Xavier LeLeu, Service des Maladies du Sang, Hôpital Huriez, Lille, France.
Table 2. Summary of Pomalidomide Studies
Abstract
Patients
Agents and Doses
Side Effects
Responses
First Author
Phase
Follow-up
Abstract 863
patients with relapsed
pomalidomide 2 mg
most patients
PR or better=26%;
M.Q. Lacy
myeloma resistant or
daily days 1 to 28
experienced
MR or better=49%;
refractory to both
(could be escalated to
hematologic toxicity;
median time to
lenalidomide and
4 mg if PD)
non-hematologic
response (TTR) 1
bortezomib; n=35
dexamethasone 40 mg toxicities included
month; DOR 12
3

---

ASH 2010 for physicians
Phase I/II
days 1, 8, 15, 22
fatigue and PN in
months; survival at 6
median F/U 9.1
full-dose aspirin or
most patients; 70%
months=78%; median
months
low-molecular-weight
PN at study entry,
survival not reached
heparin (LMWH) or
20% pomalidomide-
warfarin
related PN during
study; 2 instances of
deep vein thrombosis
(DVT) and 1
myocardial infarction
(MI)
Abstract 864
patients with
pomalidomide 21 of
grade 3 to 4
phase I: PR or greater
P.G. Richardson
myeloma refractory to 28 days with and
myelosuppression
27% for the 4 mg
lenalidomide and
without low-dose
was the dominant AE
dose, 29% for the 5
bortezomib
dexamethasone;
with low incidences
mg dose, and 25%
phase I: MTD
phase I: 2 mg (n=6), 3
of venous
overall
phase II: open label,
mg (n=8), 4 mg
thromboembolism
median OS=79.6
Arm A=
(n=14), 5 mg (n=10),
(VTE) and PN; =4 mg weeks
pomalidomide 4 mg
total enrollment,
phase II (first 120
plus low
N=38; if PD or no
efficacy evaluable
dexamethasone vs.
response after 4
patients enrolled):
Arm B=
cycles option to add
best response of at
pomalidomide 4 mg
low dexamethasone at
least PR combining
alone, endpoint is
40 mg per week
both arms by EBMT
PFS; N=221
criteria = 25% and by
IMWG criteria = 28%
Abstract 859
patients with
Arm A= 4 mg
most hematologic AE
ORR 42% for Arm A
X. LeLeu
myeloma refractory to pomalidomide and
were neutropenia;
vs. 39% for Arm B
at least 2 cycles of
low dexamethasone
some PN, and no
TTR was 2 months
lenalidomide and
for 21 days of 28 per
DVT; dose reduction
for Arm A vs. 1.7
bortezomib and a
cycle; N=43
for pomalidomide
months for Arm B
creatinine clearance
Arm B, 28 days of
was required for 49%
PR = 33% for Arm A,
(CrCl) of 50 mL/min
continuous 4 mg
in Arm A vs. 41% in
34% for Arm B
randomized phase II
pomalidomide plus
Arm B
time to progression
median follow-up 6.5
low dexamethasone;
(TTP) similar in both
for Arm A vs. 7
N=41
arms; 5 vs. 6 deaths,
months for Arm B
aspirin or LMWH
88% vs. 85% of
recommended for all
patients surviving at 6
patients
months
Elotuzumab, a monoclonal antibody (mAb)
Elotuzumab In Combination with Lenalidomide and Dexamethasone In Patients with
Relapsed Multiple Myeloma: Interim Results of a Phase II Study (Abstract 986) was
presented by Paul G. Richardson, Dana-Farber Cancer Institute, Harvard Medical School,
Boston, MA.
Elotuzumab (HuLuc63) is a humanized monoclonal antibody (mAb) targeting CS1, a cell surface
glycoprotein highly and uniformly expressed on myeloma cells, with restricted expression on
natural killer (NK) cells. In phase I studies of 5, 10, and 20 mg/kg, elotuzumab-related AEs were
primarily infusion-related in 89% patients, mostly grade 1 to 2, with no DLT, and MTD was not
reached. Median time to progression (TTP) was not reached at a median follow-up of 12.7
months. Elotuzumab saturated the CS1 binding sites in bone marrow myeloma cells at 10 mg/kg.
4

---

ASH 2010 for physicians
Objectives of phase II: to evaluate the ORR of the elotuzumab plus lenalidomide and
dexamethasone in patients with relapsed/refractory myeloma after 1 to 3 prior therapies, and to
evaluate doses of 10 and 20 mg/kg.
Doses: elotuzumab weekly for the first 4 cycles, then every other week; lenalidomide 25 mg;
low- dose dexamethasone weekly; Solu-Medrol (methylprednisolone) at the equivalent of 10 mg
of dexamethasone and other drugs to prevent infusion reactions.
Patients: no prior lenalidomide, most had a prior transplant, most had received prior
thalidomide; safety population N= 63 receiving 10 mg/kg doses (n=31) or 20 mg/kg doses
(n=32).
Side effects: The AE profile was mostly as expected with lenalidomide and dexamethasone.
Higher-grade hematologic AE were as expected and were manageable. Elotuzumab-related AE
included fatigue and low-grade fever and were manageable. There was no treatment-related
mortality. Infusion reactions occurred in 89% in the phase I portion of this trial, but with phase II
management this was cut in half. Infusion reactions were typical of those associated with mAbs.
Results: ORR was 90% with the 10 mg/kg dose. The best confirmed response of at least PR
occurred in 90% of patients on the 10 mg/kg dose and in 72% of patients on the 20 mg/kg dose.
The study was not powered to determine the differences between doses; both doses had a
sCR/CR rate of 5%. At least VGPR occurred in 37% of patients overall, and was 42% for the 10
mg/kg dose. Patients with higher beta-2-microglobulin (B2M) responded. Median time to best
response was 2 months for both arms. Median follow-up was 4.9 months, and median PFS was
not reached, which Dr. Richardson called encouraging. At both doses CS1 was saturated on
CD38+ and CD138+ cells. The 10 mg/kg dose is recommended for the open label phase III trial
to start next year.
New Targeted Therapies in Early Trials
Early trial results for two new targeted therapies in early clinical trials are summarized in Table
3. The PI3K (phosphoinositol 3 kinase) pathway is important in enhancing cell survival by
stimulating cell proliferation and inhibiting apoptosis. mTor (mammalian target of rapamycin)
inhibitors may overcome resistance to bortezomib because they are synergistic with bortezomib
in vitro and in co-culture. PD0332991 is a selective, reversible, orally bioavailable inhibitor of
cyclin-dependent kinases (CDK) 4 and 6. CDK4/6 are two positive regulatory factors involved in
the cell cycle that are associated with phosphorylation of Rb and increasing cell proliferation
with disease progression in myeloma. PD0332991 has a low toxicity and there is a reproducible
functional assay for patient samples. PD0332991 is thought to have high specificity for CDK4/6.
Induction of prolonged G1 arrest by inhibition of CDK4/6 may disrupt coupling of gene
expression from the cell cycle, thereby sensitizing cells to killing by other agents, e.g.
lenalidomide or bortezomib. Because this inhibition is reversible, release from G1 arrest may
synchronize cells and improve killing by bortezomib. Note that temsirolimus, an mTOR
inhibitor, is approved for advanced renal cell carcinoma, whereas PD0332991 is still
investigational.
mTOR (Mammalian Target of Rapamycin)
Final Results of the Phase I/II Trial of Weekly Bortezomib In Combination with
Temsirolimus (CCI-779) In Relapsed or Relapsed/Refractory Multiple Myeloma
5

---

ASH 2010 for physicians
Specifically In Patients Refractory to Bortezomib (Abstract 990) was presented by Irene M.
Ghobrial, Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston,
MA.
CDK4/CDK6 (Cell Cycle)
A Phase I Study of PD 0332991: Complete CDK4/6 Inhibition and Tumor Response In
Sequential Combination with Bortezomib and Dexamethasone for Relapsed and
Refractory Multiple Myeloma, (Abstract 860) was presented by Ruben Niesvizky, MD,
Medicine and Hematology/Oncology, Weill Cornell Medical College, New York, NY.
Table 3. Summary of New Targeted Therapy Trials
Abstract
Patients
Agents and Doses
Side Effects
Responses
First Author
Phase
Follow-up
Abstract 990
patients had 1 prior
IV temsirolimus at
phase I: the most
phase II: ORR=40%
I.M. Ghobrial
therapy and were
15 to 25 mg weekly
common AE was
excluding 3
heavily pretreated
on days 1, 8, 15, 22,
thrombocytopenia; 1
unevaluable patients;
with dexamethasone; and 29 of 35 day
death due to septic
in with bortezomib-
most had received
cycles
shock
resistant disease
thalidomide,
bortezomib at 1.3 to
phase II: toxicities
ORR=20%; in
bortezomib, and
1.6 mg/m2 weekly
included
bortezomib-sensitive
lenalidomide
on days 1, 8, 15, and
thrombocytopenia
disease ORR=53%
phase I (dose-
22
and fatigue; no
median PFS=5
escalation) n=20
dexamethasone not
sensory neuropathy
months
Phase II n=43
permitted
due to temsirolimus
median TTP=5.7
or weekly
months
bortezomib; 3 deaths
Abstract 860
patients with
PD0332991 in
schema A: DLTs
PD0332991
R. Niesvizky
symptomatic
combination with
required dose
abrogated
relapsed and/or
bortezomib and
reductions; Schema
phosphorylation of
refractory myeloma
dexamethasone,
B: DLT at the first
Rb in 80% of
after >1 treatment
given on two
dose escalation
patients; 1 patient on
who were Rb
different schedules
AEs were related to
each Schema had
positive and had
Schema A:
the combination of
VGPR
disease with a high
PD0332991 daily for
PD0332991 and
proliferation rate
21 days plus
bortezomib and
phase I dose
bortezomib and
included cytopenias
escalation study;
dexamethasone, n=9
determine MTD for
schema
Phase II
B:PD0332991 daily
for 11 days plus
bortezomib and
dexamethasone,
n=12: used for phase
II: PD0332991 will
be 100 mg,
bortezomib 1.0
mg/m2 and
dexamethasone 20
mg
6

---

ASH 2010 for physicians
Maintenance Therapy
IMF Symposium: Case Study 4: Consolidation and Maintenance Therapy in Myeloma was
presented by Phillippe Moreau, MD, University Hospital Hôtel-Dieu, Nantes, France.
Dr. Moreau discussed whether patients with VGPR after autologous stem cell transplant (ASCT)
need additional treatment, and if so, what kind. In 2009, the IMWG updated its definition of
stringent CR to require negative clonal cells by multiparametric flow cytometry (minimum of 4
colors). Stringent CR (sCR) is defined as CR plus the absence of phenotypically aberrant plasma
cells in the bone marrow with a minimum of 3000 total plasma cells analyzed by multiparametric
flow cytometry ("immunophenotypic CR"). Molecular CR was also incorporated into the IMWG
(the IMF-sponsored International Myeloma Working Group) criteria and is defined as stringent
CR plus negative ASO-PCR (allele-specific oligonucleotide polymerase chain reaction). Because
depth of response and time to progression are correlated, it is important to identify the best
consolidation therapy after ASCT. The BMT-CTN phase III study will randomly assign patients
to no consolidation vs. consolidation with VRD x 4 or with Mel (melphalan); all patients receive
Mel 200 so the Mel consolidation is a second ASCT. All groups will then receive lenalidomide
maintenance. The new IMWG criteria will be used to assess response.
Dr. Moreau reviewed published and on-going studies of maintenance therapy. IFM 2005-02
supports lenalidomide maintenance after ASCT, showing improved PFS but no OS advantage.
The CALGB 100104 study is an ongoing phase III trial of lenalidomide vs. placebo as
maintenance after ASCT. PFS and TTP are improved in the lenalidomide arm but there is no
difference in OS (see below). The HOVON-65/GMMG-HD4 is another ongoing phase III trial.
An additional trial, MM-015, is comparing melphalan plus prednisone plus lenalidomide
followed by lenalidomide maintenance (MPR-R) vs. MPR vs. MP for long-term control in newly
diagnosed myeloma. PFS at the first interim analysis showed a 50% reduction risk. MPR-R vs.
MPR in a landmark analysis of PFS after cycle 9 showed a 75% reduced risk. Again, there is no
difference in OS. The FIRST study of lenalidomide and low-dose dexamethasone vs. MPT (MP
plus thalidomide) (IFM 07-01) included almost 1600 patients and just closed to enrollment.
Lenalidomide and low-dose dexamethasone until progression is being tested in one arm. During
the discussion, it was noted that lenalidomide maintenance outside of the clinical trial setting is
allowed in the US but not in Italy, France, or Spain. Data supporting bortezomib maintenance
therapy have also been presented. How long to give maintenance therapy is not known.
The results of three maintenance studies are summarized in Table 4.
Thalidomide Maintenance Significantly Improves Progression-Free Survival (PFS) and
Overall Survival (OS) of Myeloma Patients When Effective Relapse Treatments Are Used:
MRC Myeloma IX Results (Abstract 623) was presented by Gareth J Morgan, Institute of
Cancer Research, The Royal Marsden Hospital, London, United Kingdom.
Maintenance Treatment with Lenalidomide After Transplantation for Myeloma: Final
Analysis of the IFM 2005-02 (Abstract 310) was presented by Michel Attal, MD, Hôpital
Purpan, Toulouse, France.
Phase III Intergroup Study of Lenalidomide Versus Placebo Maintenance Therapy
Following Single Autologous Hematopoietic Stem Cell Transplantation (AHSCT) for
Multiple Myeloma: CALGB 100104 (Abstract 37) was presented by Philip L. McCarthy, MD,
BMT Program, Roswell Park Cancer Institute, Buffalo, NY.
7

---

ASH 2010 for physicians
Table 4. Summary of Maintenance Studies
Abstract
Patients
Agents and Doses
Side Effects
Responses
First Author
Phase
Follow-up
Abstract 623
820 patients
thalidomide or no
high rate of PN led
PFS significantly
G. Morgan
maintenance (half to
to slightly over half
longer for patients
each arm)
of patients
on thalidomide
median 7 months of
discontinuing
maintenance overall
maintenance
maintenance
with most benefit for
those with favorable
FISH; no difference
in OS
Abstract 310
614 patients under
placebo (n=307) or
discontinuation rate
CR and PFS
M. Attal
age 65 years with
lenalidomide
15% for placebo vs.
improved with
non-progressive
(n=307)
21% with
lenalidomide
disease within 6
maintenance therapy
lenalidomide;
maintenance
months of ASCT;
lenalidomide caused
4 factors associated
phase III
significant non-
with improved PFS:
median F/U 34
febrile neutropenia,
lenalidomide
months post-random
and 2% DVT vs. 0
maintenance, VGPR
assignment
for placebo
after consolidation
recommendation to
(most important), no
monitor for second
del 13, and low 2M
malignancies
no differences in OS
5 years post-
diagnosis between
groups (80%).
Abstract 37
patients with stable
placebo (n=229) or
lenalidomide
lenalidomide
P. McCarthy
disease (SD) or
lenalidomide
maintenance
associated with 60%
better within a year
maintenance
associated with
reduction in the risk
of induction therapy
(n=231) at a starting
significantly more
of disease
and ASCT Mel 200
dose of 10 mg/day,
AE, including
progression or death
escalated to 15
thrombocytopenia,
vs. placebo
mg/day after 3
neutropenia, febrile
median TTP for
months, and
neutropenia, and
lenalidomide = 42.3
continued until PD,
infections
months vs. 21.8
with dose reductions
15 new malignancies
months for placebo
or discontinuation if
after randomization
TTP independent of
necessary for
in patients receiving
2M levels or prior
toxicity
lenalidomide vs. 6 in
lenalidomide or
the placebo arm
thalidomide
OS not yet published
Myeloma Biology
Bisphosphonates and Bone Disease
There were two presentations on sub-analyses of the MRC Myeloma IX trial concerning
myeloma bone disease.
8

---

ASH 2010 for physicians
Optimising Bone Disease In Myeloma; Zoledronic Acid Plus Thalidomide Combinations
Improves Survival and Bone Endpoints: Results of the MRC Myeloma IX Trial (Abstract
311) was presented by Gareth J Morgan, Section of Haemato-Oncology, The Institute of Cancer
Research, London, United Kingdom.
Objectives: This presentation focused on randomization to zoledronic acid or clodronate in both
treatment arms (intense and non-intense) in the MRC Myeloma IX trial. Note that zoledronic
acid is available in the US, but clodronate is not (although it is available in Canada, the UK, and
other countries).
Patients: Approximately 1960 patients were enrolled in this study; median follow-up is 3.7
years.
Side effects: There was no excess renal toxicity. Osteonecrosis of the jaw (ONJ) was
significantly higher with zoledronic acid, about 4%, but all incidents were minor and resolved
without surgery and with conservative management.
Results: Zoledronic acid was associated with significantly improved OS (5.5 month increase) vs.
clodronate, and PFS was also increased. Adjustment for skeletal-related events (SRE; defined as
pathologic fractures, need for radiation to the bone, bone surgery, spinal cord compression, and
similar events) still favors zoledronic acid, suggesting an anti-myeloma effect. Zoledronic acid
was associated with higher OS and longer PFS for both intensive and non-intensive treatment
groups, although the difference was not significant for the intensive pathway. Zoledronic acid
significantly reduced SRE for patients with bone lesions at presentation and for those with no
lesions at baseline, suggesting that all patients should be treated even if they have no bone
lesions at baseline. Zoledronic acid decreased SRE compared with clodronate during
maintenance therapy, and was better than clodronate regardless of induction regimen. Patients
receiving thalidomide-containing regimens plus zoledronic acid had the best responses.
Defining Myeloma Patients at High Risk of Developing Bone Disease While on
Bisphosphonate Treatment (Abstract 782) was presented by Ping Wu, Section of Haemato-
Oncology, The Institute of Cancer Research, London, United Kingdom.
Objectives: This analysis investigated the molecular basis of bone disease at presentation, and
developed a gene expression-based predictor applicable to patients with myeloma at presentation
for high risk of developing myeloma bone disease.
Methods: Gene expression profiling (GEP) was performed on samples from 261 patients
comprising a training set (n=205) and test set (n=56). Differential expression of genes was
scored by SAM (significance analysis of microarray).
Results: There was a shorter OS in patients presenting with bone disease defined by presence of
any lytic lesion or x-ray indication. There were 50 genes associated with bone disease at
presentation by SAM score. Of those that were up-regulated, most were involved with growth
factors, apoptosis, and transcription factor regulation. This suggests that patients with bone
disease have a different myeloma metabolism. The top 10 genes most significantly associated
with bone disease at presentation included DKK1 (Wnt signaling inhibitor), RNASEH2B
(involved in DNA replication), genes involved in apoptosis, and 2 genes associated with growth
factor signaling. FRZB and DKK1 are both up-regulated. In the group of patients with low bone
disease, these genes are both down-regulated. Insulin-like growth factor (IGF)-1 is one of the
growth factors involved in bone destruction. Two negative regulators of IGF signaling are down-
9

---

ASH 2010 for physicians
regulated with bone disease. The time to first SRE (TTFSRE) curve shows rapid onset of events
within the first two months for patients treated with zoledronic acid or clodronate in the MRC
trial, so they looked at this point of the curve; the SREs level off after this point. There was a
26% relative reduction in all events with zoledronic acid within the first 2 months, which may be
related to disease control. Excluding the first 2 months, 97% of patients had their first SREs
within 2 months to 2 years. Of the 14 genes identified as associated with SRE development, all
are up-regulated in SRE. These include interferon-induced genes reported by UAMS to be
associated with poor prognosis.
A 7-gene signature for SRE was developed that has good predictive power. Looking at all
patients in the trial, other SRE-associated parameters included t(4;14), hyperdiploidy, presenting
bone disease, and high calcium levels. In the gene expression data set high calcium, presenting
bone disease, and hyperdiploidy were significantly associated with SRE development; when
added individually to the 7-gene signature, only calcium was statistically significant. The
sensitivity and specificity of the training set were 87% and 72% respectively; these were
validated in the test set. The SRE predictor, which includes the 7 genes plus calcium, is clinically
applicable to estimating the risk of SRE before relapse despite a patient being on bisphosphonate
treatment. This was validated in subgroups of patients with and without baseline bone disease
treated with and without zoledronic acid or clodronate. The genes identified give insight into the
biology of underlying SRE development. This test could be used in future clinical trials to
identify patients at high risk for bone disease even while on bisphosphonates.
Renal Impairment
Meletios A. Dimopoulos, Greek Myeloma Study Group, Greece, presented Renal Insufficiency
and Failure as part of the Multiple Myeloma Education Program: Supportive Care in
Plasma Cell Dyscrasias, chaired by Pieter Sonneveld, MD, PhD, Erasmus University Medical
Center, Rotterdam, Netherlands.
The main points include the following:
Renal function should be assessed in patients with myeloma. Diagnosis involves evaluation
of serum creatinine, urinary Na, K, Ca, calculation of estimated glomerular filtration rate
(eGFR) using the MDRD formula, determination of total protein in a 24-hour urine sample,
urine protein electrophoresis (UPEP) and immunofixation, and serum free light chains
(FLC).
Management of myeloma-associated renal dysfunction includes hydration, alkalinizing the
urine, managing hypercalcemia, treating infections, and avoiding nephrotoxic agents while
managing the myeloma. High-dose steroids may be effective. Plasma exchange with
hemodialysis or hemodialysis alone does not appear to be very effective, although high cut-
off permeability filters could remove large amounts of FLC.
Doses of melphalan should be reduced with renal impairment.
Thalidomide has negligible renal excretion, so it can be used in patients with renal
dysfunction, but there are case reports of associated hypokalemia. Thalidomide may reverse
renal impairment in some patients.
Because lenalidomide is primarily excreted by the kidneys, dose reduction, based on
creatinine clearance (CrCl) is mandatory in renal impairment.
10

---

ASH 2010 for physicians
There is a strong rationale for using bortezomib in patients with renal impairment.
Pharmacokinetics are independent of renal function, there is a rapid response, and
bortezomib is generally well tolerated; about 50 to 60 % of patients experience improved
renal function. Dialysis may be avoided or no longer required in some patients treated with
bortezomib. Improved renal function has also been seen in bortezomib-based combination
therapy. Bortezomib should be given after dialysis.
IMWG proposes bortezomib-based therapy in patients with renal impairment with high-dose
dexamethasone, possibly with the addition of a third agent, e.g., thalidomide,
cyclophosphamide, or doxorubicin, and is recommended for patients with renal impairment
of any grade.
Targeting the Myeloma Stem Cell
Ad Hoc Scientific Committee on Plasma Cell Biology: Targeting the Myeloma Stem Cell.
Chair Raymond Powles, Parkside Oncology Clinic, Wimbledon, United Kingdom, said that the
committee will change its name to Plasma Cell Neoplasia.
William Matsui, MD, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins
University School of Medicine, Baltimore, MD, presented The Origin of the Myeloma Stem
Cell (SCI-4), and discussed the concept of myeloma cancer stem cells. His main points include
the following:
Clonogenic tumor cells are rare. Relapse in cancer requires chemoresistance and clonogenic
potential. It is possible that chemotherapy removes tumor cells but cancer stem cells have
intrinsic drug resistance. It is not clear if tumorigenic cells in myeloma are involved in
initiation, relapse, or progression.
Patient-specific factors, including disease stage and type (MGUS, myeloma, PCL), whether
newly diagnosed or relapsed, as well as genetics, e.g., presence of hyperdiploidy vs. Ig-
translocations, affect the ability to isolate putative myeloma stem cells.
To identify potential targets of small molecules that might be used to attack myeloma stem
cells, a discovery approach using GEP and proteomics is required. For this, a homogenous
cell population is needed and it has not been possible to achieve this yet in any cancer.
Treatment of myeloma requires targeting two compartments: plasma cells and stem cells. It
has been reported that Rituximab could target stem cells; if it did so in myeloma, then
cyclophosphamide could be used to debulk plasma cells, followed by more Rituximab for
residual stem cells.
There is a need for novel clinical trial designs to detect activity against the small population
of tumor cells. Stem cell-based biomarker strategies need to be developed.
Martin Pérez Andrés, PhD, Universidad de Salamanca, Salamanca, Spain, discussed
Immunophenotypic Analysis of Myeloma Precursors: Antigens for Therapeutic Targeting
(SCI-5). He proposed three features that all tumor stem cells should have: ability to differentiate,
ability to self-renew, and resistance to therapy. He reviewed properties of putative myeloma
precursor cells, reiterating that the clonogenic fraction is small. The strongest evidence for them
is the ability to reproduce tumors in vitro and in vivo. He believes these cells have features of
11

---

ASH 2010 for physicians
germinal center cells, that is, B cells not plasma cells, although not everyone agrees. His
hypothesis is that a precursor cell in the plasma cell compartment needs to circulate to spread
throughout bone marrow. Another hypothesis is that the cells derive from memory B cells.
Whatever model is correct, it should be possible to find myeloma precursor cells in the
peripheral blood, in part because in aggressive and end-stage disease, extramedullary disease
occurs as a result of spread via the circulation. There is some evidence that important
tumorigenic activity is occurring within the plasma cell compartment.
Constantine S. Mitsiades, MD, PhD, Jerome Lipper Multiple Myeloma Disease Center, Dana-
Farber Cancer Institute, Harvard Medical School, Boston, MA, presented How to Overcome
Myeloma Stem Cell Resistance to Therapy - Targeting the Stem Cell Niche (SCI-6). The
main points of this presentation include the following:
Mechanisms of drug resistance in myeloma include differential dependence on oncogenic
pathways compared with the bulk of the tumor population, e.g., hedgehog, notch, and Wnt
signaling pathways. These pathways all have multiple ligands and receptor proteins, are
complex, and interact with each other, providing multiple points in these pathways that can
be targeted in myeloma and other cancers. Agents targeting these pathways are in clinical
development. Although mutations activating these pathways seem to occur in other cancers,
they have not been seen in myeloma.
A caveat to targeting developmental pathways in cancer stem-like cells is that agents
developed to do so may have side effects on normal stem cells.
There is an additional need to screen agents against the myeloma stem cells in the presence
of accessory (stromal) cells. Some developmental pathways or cancer stem cell pathways
seem to be more active in the presence of bone marrow stromal cells (BMSC), maybe
because they target the interactions or have multi-target effects. Any agent targeting
"stemness" needs to be tested in the presence of the local microenvironment.
It is not known if most of the tumor is capable of reverting back to stem cell-like cells, and if
there is bi-directional transition of tumor cells between stem cell-like and non-stem cell-like
states, likewise between drug resistant and non-resistant states, and if these are influenced by
the microenvironment.
Side Effects of Therapy
Neuropathy
Pieter Sonneveld, MD, PhD, Department of Hematology, Erasmus University Medical Center,
Rotterdam, Netherlands, presented Dealing with Neuropathy as part of the Multiple Myeloma
Education Program: Supportive Care in Plasma Cell Dyscrasias, which he chaired. The talk
is summarized here. Important points include the following:
In all plasma cell diseases, up to 54% of newly diagnosed patients, including those with
MGUS, myeloma, POEMS, and Castleman disease, have peripheral neuropathy (PN). PN is
also associated with amyloidosis and cryoglobulinemia.
The causes of baseline PN in myeloma include mechanical compression of nerves, including
the spinal cord; radiculopathy; carpal tunnel syndrome; hyperviscosity; diabetes; vitamin
12

---

ASH 2010 for physicians
deficiencies, e.g., of B12; and possibly genetic susceptibility.
Treatment with vincristine and cisplatin, which are not used much any more in myeloma,
thalidomide, and to a lesser extent lenalidomide and pomalidomide, and the proteasome
inhibitors bortezomib and carfilzomib, are associated with PN. PN is one of the most
frequent non-hematologic side effects of myeloma therapy and has a serious impact on
patient QoL, including physical, social, and psychological functions. It is also frustrating for
the physician, and may interfere with patients continuing therapy.
The anatomic damage caused by thalidomide and bortezomib are different. Axons are
damaged more by thalidomide, whereas bortezomib is toxic to small afferent fibers.
Carfilzomib causes less sensory PN (less than 15%) than bortezomib.
Thalidomide causes mixed sensory motor PN with degeneration of the longest axons, inhibits
vascular supply to nerves, and leads to demyelination, which may be irreversible.
Thalidomide-emergent PN can be predominantly sensory or sensorimotor, with symmetric
hypoesthesia, tingling, or hyperesthesia of the fingers and toes. Motor PN occurs less
frequently than sensory PN. Symptoms such as cramps, weakness, or tremor must be
differentiated from steroid-induced effects in patients taking thalidomide with steroids.
Bortezomib-emergent PN is typically sensory, and presents as hyperesthesia, hypoesthesia,
tingling, or temperature sensitivity, and causes burning sensations in the soles and palms,
starting distally with possible progression to proximal PN. Bortezomib-associated motor PN,
if present, follows sensory PN. Autonomic PN may present as orthostatic hypotension, sexual
dysfunction, or constipation, and generally appears and progresses slowly. Lower bortezomib
doses are associated with a lower incidence of PN.
Both thalidomide and bortezomib-associated PN are time dependent and dose dependent. PN
associated with thalidomide is minimally reversible, and takes years to resolve. Bortezomib-
associated PN improves or resolves in 2 to 3 months in 70% of patients. To manage PN,
doses of bortezomib or thalidomide should be modified.
The key to intervention is prevention, because there is little treatment, and prevention is more
important than medication. Vitamin C may interfere with bortezomib efficacy. Tricyclic
antidepressants, anti-seizure medications, selective serotonin norepinephrine reuptake
inhibitors (SSNRIs), calcium channel blockers, and other agents have been used to treat PN.
Supplements, vitamins, and minerals are sometimes recommended, but have not been tested
in clinical trials.
Two studies assessing peripheral neuropathy are summarized in Table 5.
Development of Bortezomib-Induced Peripheral Neuropathy (BiPN) In Multiple Myeloma:
Incidence and Molecular Characterization In Newly Diagnosed Patients Treated with
Bortezomib (Abstract 304) was presented by Annemiek Broyl, MD, Hematology, Erasmus
MC, Rotterdam, Netherlands.
A Phase III Prospective Randomized International Study (MMY-3021) Comparing
Subcutaneous and Intravenous Administration of Bortezomib In Patients with Relapsed
Multiple Myeloma (Abstract 312) was presented by Philippe Moreau, University Hospital,
Nantes, France.
Table 5. Summary of Peripheral Neuropathy Studies
13

---

ASH 2010 for physicians
Abstract
Patients
Agents and
Side Effects
Results
First Author
Phase
Doses
Follow-up
Abstract 304
patients with
induction therapy
incidence of early onset
Early onset BiPN was
A. Broyl
myeloma (n=369)
with bortezomib
bortezomib-induced PN
associated with genes
phase III prospective,
(PAD; n=250)
(BiPN) (within one
involved in drug-
randomized trial
followed by
treatment cycle) in the
induced apoptosis,
(HOVON65/GMMG-
bortezomib
bortezomib-treated
peripheral nervous
HD4) sub-study to
maintenance vs.
patients was not
system development
analyze genetic
conventional
significantly different
and function, DNA
variation associated
vincristine (VAD;
from the incidence of
repair, mitochondrial
with BiPN the "Bank
n=250) induction
early onset vincristine
dysfunction, and
on a Cure" (BOAC)
therapy followed
induced PN (ViPN) in
AMPK signaling. Late-
SNP chip, containing
by thalidomide
VAD-treated patients
onset BiPN was
3404 SNPs in
maintenance
late onset (after cycle 2
associated with
functional regions
to 3); BiPN was
different genes involved
within 983 cellular
significantly greater
in peripheral nervous
function genes and
(grade 2 to 4) than
system development
pathways
ViPN, 25% vs. 7%
and function, apoptosis,
calcium ion binding,
inflammation,
transcription regulation,
and DNA repair. ViPN
was associated with
different genetic
factors.
Abstract 312
74 patients in the IV
subcutaneous
grade 3 and 4 AE were
ORR=42% in both arms
P. Moreau
arm, 148 patients in
(SC) bortezomib
reduced, but not
after 4 cycles
the SC arm
(2.5 mg/mL) vs.
statistically
VGPR for IV = 16%
IV bortezomib (1
significantly with SC:,
vs. 17% for SC
phase III randomized
mg/mL) at the
57% for SC and 70%
After 8 cycles 52%
study
usual dose and
for IV
ORR and 25% VGPR
schedule
neutropenia
for both arms
dexamethasone
significantly reduced
median TTR=1.4
after 4 cycles if
with SC administration;
months in both arms
response was PR
thrombocytopenia and
median TTP=9.4
anemia the same for SC
months for IV and 10.4
and IV
months for SC
PN statistically
1 year survival=76% for
significantly different:
IV and 73% for SC
any PN 53% with IV
PK and
vs. 38% with SC;
pharmacodynamics are
grade 2 PN 41% with
the same, and
IV vs. 24% with SC;
differences in Cmax
grade 3 PN 16% with
and Tmax might
IV and 6% with SC.
explain the improved
Local site reactions
safety profile with the
(redness) in 6% of
SC route
patients; 1% of patients
had a severe site
reaction
14

---

ASH 2010 for physicians
Thrombosis
Sigurdur Y. Kristinsson, MD, PhD, Department of Medicine, Division of Hematology,
Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden, presented
Thrombotic Issues in Myeloma as part of the Multiple Myeloma Education Program:
Supportive Care in Plasma Cell Dyscrasias, chaired by Pieter Sonneveld, MD, PhD, Erasmus
University Medical Center, Rotterdam, Netherlands. The main points were:
Patients with cancer, including myeloma, have an increased risk for both venous and arterial
thrombosis.
Thalidomide and lenalidomide increase the risk of venous thromboembolism (VTE).
Thalidomide is associated with an increased risk in combination chemotherapy, particularly
in newly diagnosed patients; lenalidomide increases the risk in combination with
dexamethasone or chemotherapy in either newly diagnosed or relapsed, refractory myeloma.
Arterial thrombosis occurs in younger patients with myeloma treated with VAD, TAD, or
PAD.
Bortezomib does not cause an increase risk of VTE alone or in combination with
dexamethasone or chemotherapy in newly diagnosed or relapsed, refractory myeloma. There
have been suggestions that bortezomib has a protective effect in combination with
lenalidomide or thalidomide but patients in many studies have been given anti-thrombotic
prophylaxis.
Thrombotic events associated with ASCT may be related to the use of central venous
catheters.
Published guidelines from the IMWG suggest aspirin for patients with no risk factors and
LMWH or full-dose warfarin for those with two or more risk factors. Duration of
thromboprophylaxis depends on patient- and treatment-related risk factors. Risk is highest at
the beginning of treatment, so prophylaxis for 4 to 6 months at least is suggested. There are
no studies of thromboprophylaxis in patients with myeloma and renal failure, but if CrCl is
less than 30 mL/min, it is best to dose adjust LMWH or use warfarin.
Treatment of VTE includes stopping thalidomide or lenalidomide, administering full
anticoagulation with LMWH or warfarin, and then restarting anti-myeloma therapy.
Newly Diagnosed Myeloma
Transplant-Eligible Patients
IMF Symposium Case 2: Evolving Treatment Approaches in Transplantation-Eligible
Patients was presented by Jesús F. San Miguel, MD, PhD, Hospital Universitario de Salamanca,
Salamanca, Spain.
Controversial issues concerning treatment of young patients with myeloma include the optimal
induction treatment, the role of high-dose therapy and ASCT, the value of maintenance therapy,
treatment according to risk stratification, and the role, if any, for allogeneic transplant. The main
points of this presentation were:
15

---

ASH 2010 for physicians
Induction regimens with bortezomib, thalidomide, or lenalidomide yield better responses and
longer PFS than VAD.
Induction with novel agents and ASCT are complementary, but conditioning regimens can be
improved by adding bortezomib to melphalan; busulfan plus melphalan is showing
promising results.
The IFM-DFCI trial should answer the question about early vs. late ASCT. Patients receiving
early transplant appear to have a higher 3-year OS than those who continued on primary
therapy. With up-front transplant patients are more likely to tolerate intensive and
repetitive therapies. ASCT is associated with a long treatment-free interval and good
QoL, and although relapsed myeloma after high-dose (HD) Mel is sensitive to novel
agents, it isn't known whether relapsed myeloma after novel therapies is sensitive to HD
Mel.
In general, thalidomide, lenalidomide, and bortezomib as maintenance therapy have shown
benefits.
Treatment stratification according to risk factors would offer intensive treatment to patients
with high-risk disease, and less intense approaches for patients with lower-risk disease or
for those who are in CR. If there is no molecular remission, there is a higher risk of
relapse. If cure is the goal, under-treating low-risk patients may not be the best approach
because they should be the first group of patients who could be cured. Better tools to
evaluate treatment efficacy are needed.
A particular regimen can't be recommended for high-risk disease based on current data, and
trials are needed.
Rather than using allogeneic transplantation, Dr. San Miguel recommends induction with a
novel combination, e.g., VRD with or without cyclophosphamide, ASCT with Mel 200
plus bortezomib; then if the patient has CR, maintenance with lenalidomide; if no CR,
then consolidation with VRD, then maintenance.
Four studies in transplant-eligible, newly diagnosed patients with myeloma are
summarized in Table 6.
A Phase III PETHEMA/GEM Study of Induction Therapy Prior Autologous Stem Cell
Transplantation (ASCT) In Multiple Myeloma: Superiority of VTD
(Bortezomib/Thalidomide/Dexamethasone) Over TD and VBMCP/VBAD Plus Bortezomib
(Abstract 307) was presented by Dr. Laura Rosiñol, Hospital Clinic, Barcelona, Spain.
Frontline Therapy with Bortezomib, Lenalidomide, and Dexamethasone (VRD) Induction
Followed by Autologous Stem Cell Transplantation, VRD Consolidation and Lenalidomide
Maintenance In Newly Diagnosed Multiple Myeloma Patients: Primary Results of the IFM
2008 Phase II Study (Abstract 624) was presented by Murielle Roussel, Hématologie Clinique,
Hôpital Purpan, Toulouse, France.
16

---

ASH 2010 for physicians
Molecular Remission After Bortezomib-Thalidomide-Dexamethasone Compared with
Thalidomide-Dexamethasone as Consolidation Therapy Following Double Autologous
Transplantation for Multiple Myeloma: Results of a Qualitative and Quantitative Analysis
(Abstract 861) was presented by Carolina Terragna, Seràgnoli Institute of Hematology, Bologna
University School of Medicine, Bologna, Italy.
Tandem Autologous Hematopoietic Stem Cell Transplants (AuHCT) with or without
Maintenance Therapy (auto-auto) Versus Single AuHCT Followed by HLA Matched
Sibling Non- Myeloablative Allogeneic HCT (auto-allo) for Patients with Standard-Risk
(SR) Multiple Myeloma (MM): Results From the Blood and Marrow Transplant Clinical
Trials Network (BMT CTN) 0102 Trial (Abstract 41) was presented by Amrita Krishnan,
M.D., Hematology and Stem Cell Transplantation, City of Hope, Duarte, CA.
Table 6. Summary of Studies in Transplant-eligible, Newly Diagnosed Patients
Abstract
Patients
Agents and Doses
Side Effects
Results
First Author
Phase
Follow-up
Abstract 307
390 patients (130 per n=129 for QT +V
grade 3 to 4 adverse
CR was significantly
L. Rosinol
arm)
(conventional
events were similar
higher with VTD
GEM05 MENOS65
chemotherapy:
among the arms;
(35%) than QTD
median F/U = 27
VBMCP/VBAD
neutropenia was
(21%) or TD (14%);
months
plus bortezomib),
higher for QT+V
post-ASCT CR was
n=127 for TD,
PN was higher with
38% for QT+V, 24%
n=130 for VTD
VTD
for TD, and 48% for
VTD;
CR for patients with
t(4;14) was higher
with VTD;
CR for patients with
t(11;14) was better
with QT+V;
OS at 4 years was
76% with no
significant
differences across
groups but was
shorter for high-risk
patients regardless of
treatment
Abstract 624
newly diagnosed
VRD induction, SC
almost all patients
RR improved with
M. Roussel
younger patients
collection, ASCT
experienced
each stage of
(n=31)
with HD Mel,
hematologic
treatment;
phase II open label
consolidation with
toxicities; grade 3 to
VGPR was over
(IFM 2008)
VRD,
4 events included
80%; CR in almost
maintenance for 12
39% neutropenia
half of patients
months with
(decreased to 26%
lenalidomide at a
with dose reduction),
dose of 10 mg for 3
13%
17

---

ASH 2010 for physicians
months; if tolerated,
thrombocytopenia,
the dose was
and 6% anemia;
increased to 15 mg
PN in 68% of
per day continuous
patients, 55% during
induction, 13%
during
consolidation, all
grade 1 and 2,
requiring bortezomib
dose reduction in
23%;
2 TE;
5 needed second-line
mobilizing agent for
SC collection;
collection not
possible in one
patient
Abstract 861
young, newly
VTD vs. TD for
Results
C. Terragna
diagnosed patients
induction prior to
sub-study of
ASCT
TD arm: 10 of 32 (31%) PCR negative at
GIMEMA looking
random assignment
baseline; at consolidation 15 of 31 (48%)
for minimal residual
to consolidation with
were PCR negative; at F/U, MCR was
disease (MRD) in
VTD (n=34) or TD
37.5%; 41% had persistently positive PCR.
bone marrow at
(32) after ASCT;
VTD arm: 13 of 33 (39%) PCR negative at
consolidation using
maintenance for
baseline; at consolidation 21 of 32 (64%)
patient-specific IgH
both arms
were PCR negative; MCR was 45.5%, and
gene rearrangements
21 % of patients were persistently PCR
and patient-specific
positive.
PCR (two primers
An upgrade in PCR-negative status after
designed for each)
consolidation occurred with VTD but not
TD. PFS was significantly longer for
patients who were PCR negative at
consolidation
Abstract 41
patients biologically
initial ASCT with
treatment-related
84% of patients
A. Krishnan
assigned to ASCT
HD Mel 200 then
mortality (TRM) at 3 assigned to
(n=436) or to
ASCT or alloSCT on years was
thalidomide
alloSCT (n=189) on
basis of donor
significantly higher
maintenance did not
the basis of
graft-versus-host
in the ASCT-
complete it.
availability of an
disease (GvHD);
alloSCT group
PFS and OS were
eligible, HLA-
prophylaxis was
(12%) than in the
similar and results
matched sibling
cyclosporine and
tandem ASCT group
were pooled for all
donor after ASCT
mycophenolate
(4%)
tandem ASCT
phase III
mofetil.
patients;
If tandem ASCT,
after the first ASCT,
random assignment
3-year PFS was
to maintenance with
similar between
thalidomide plus
groups (46% for
dexamethasone
tandem ASCT vs.
(n=217) or
43% for ASCT-
observation (n=219)
alloSCT), and 3-year
for one year
OS was 80% vs.
77%.
No significant
difference in 3-year
18

---

ASH 2010 for physicians
progression/relapse
between the tandem
ASCT (46%) and
ASCT-alloSCT
(40%) groups
Transplant-Ineligible Patients
IMF Symposium Case Study 3: Emerging Therapies for Transplantation-Ineligible
Patients was presented by Antonio Palumbo, MD, University of Torino and Italian Multiple
Myeloma Study Group, Torino, Italy. The main points were:
For patients who are not eligible for ASCT, use combinations up front, especially novel
agent combinations, because the disease is more likely to be sensitive and there is a
higher chance of longer survival.
PFS is longer with molecular response, e.g., PCR negative. All CR are not the same.
Combination therapy may increase the CR rate via profound cytoreduction, whereas
continuous therapy prolongs PFS. CR predicts the long-term outcome in elderly patients.
Toxicity of maintenance therapy with lenalidomide or bortezomib in elderly patients
might reduce survival.
The standard of care for elderly patients should be addition of a novel agent to MP, e.g.,
MPT (increases PFS and OS, but requires prophylaxis for VTE) or VMP (once-weekly
bortezomib as part of VMP does not decrease PFS or OS, and is associated with lower
rates of PN and discontinuation). VMPT-VT and MPR are other options, but not for
patients over age 75 years because increased dose intensity means increased toxicity and
discontinuation. Those age 75 years and above should receive reduced-dose
chemotherapy. Further dose reductions may be necessary based on AE.
Five studies in transplant-ineligible patients with myeloma are summarized in Table 7.
Lenalidomide Plus Low-Dose Dexamethasone (Ld): Superior One- and Two-Year Survival
Regardless of Age Compared to Lenalidomide Plus High-Dose Dexamethasone (LD)
(Abstract 308) was presented by Dr. David H. Vesole, John Theurer Cancer Center at
Hackensack University Medical Center, Hackensack, NJ.
Phase 3b UPFRONT Study: Safety and Efficacy of Weekly Bortezomib Maintenance
Therapy After Bortezomib-Based Induction Regimens In Elderly, Newly Diagnosed
Multiple Myeloma Patients (Abstract 619) was presented by Ruben Niesvizky, Center of
Excellence for Lymphoma and Myeloma, Weill Cornell Medical College, New York
Presbyterian Hospital, New York, NY.
Bortezomib, Melphalan, Prednisone and Thalidomide Followed by Maintenance with
19

---

ASH 2010 for physicians
Bortezomib and Thalidomide (VMPT-VT) for Initial Treatment of Elderly Multiple
Myeloma Patients: Updated Follow-up and Impact of Prognostic Factors (Abstract 620)
was presented by Antonio Palumbo, Myeloma Unit, Division of Hematology, University of
Torino, Torino, Italy.
Novel Three- and Four-Drug Combination Regimens of Bortezomib, Dexamethasone,
Cyclophosphamide, and Lenalidomide for Previously Untreated Multiple Myeloma:
Results From the Multi-Center, Randomized, Phase II EVOLUTION Study (Abstract 621)
was presented by Shaji Kumar, MD, Division of Hematology, Mayo Clinic, Rochester, MN.
A Phase III Study Evaluating the Efficacy and Safety of Lenalidomide Combined with
Melphalan and Prednisone In Patients 65 Years with Newly Diagnosed Multiple
Myeloma (NDMM): Continuous Use of Lenalidomide Vs Fixed-Duration Regimens
(Abstract 622) was presented by Antonio Palumbo, MD, University of Torino, Torino, Italy.
Table 7. Summary of Studies in Transplant-ineligible Patients
Abstract
Patients
Agents and Doses
Side Effects
Responses
First Author
Phase
Follow-up
Abstract
newly diagnosed
LD (lenalidomide
toxicity was higher in all
OS for Ld was superior
308
patients
plus high dose
age groups receiving
to that of LD at 1 and 2
D. Vesole
ECOG study
dexamethasone) vs.
high- dose
years
E4A03
Ld (lenalidomide plus
dexamethasone
OS across all age groups
low dose
using an age-smoothing
dexamethasone)
technique to correct for
survival of patients
age as a continuous
treated with LD was
variable; by this method,
inferior at the initial
there is no age group for
analysis so those on
which high-dose
LD crossed over to
dexamethasone is
Ld, which is a
superior
confounding variable
LD results in a higher
for a long-term study
RR in patients under age
65 years but not
improved PFS or OS
Abstract
newly diagnosed
8 cycles of induction
for the first 100 patients
PFS for the three arms is
619
elderly patients
therapy and 6 cycles
treatment-emergent grade
similar, around 13 to 17
R. Niesvizky
ineligible for
maintenance
3 or more AE were high;
months, but these are
transplant in the
VD ("classic"
PN was significant,
early results;
context of a
bortezomib and
especially with VTD,
global health improved
community
dexamethasone) vs.
which was also
at the time of
oncology practice
VTD (bortezomib and
associated with the
maintenance, and the
(n=502 for ITT
dexamethasone on the
highest rate of AE
best QoL was seen for
population)
same classic schedule
overall; grade 3 or higher
the VMP group (poster
F/U is ongoing
plus 100 mg
PN was 15%, 26%, and
Abstract 3026)
thalidomide) vs. VMP
20% for VD, VTD, or
(bortezomib on the
VMP, respectively, and
same schedule,
the respective
20

---

ASH 2010 for physicians
melphalan and
discontinuation rates
prednisone on the
were 7%, 17%, and 18%;
first 4 days of every
serious AE (SAE)
other cycle)
included pneumonia and
maintenance with 1.6
thrombosis associated
mg/m2 of bortezomib
with VT;
once weekly for 4
during maintenance there
weeks out of every 5
was no increase in
toxicities, including PN
or SAE
Abstract
patients over age
VMP and no
VMPT increases
CR = 24% for VMP, and
620
65 years (n=511);
maintenance (n=257)
neutropenia to 35%,
42% for VMPT
A. Palumbo
median
vs. VMPT, adding 50
thrombocytopenia and
(statistically significant
maintenance
mg continuous
anemia are similar for
difference)
duration of 18
thalidomide for 9
both treatments;
no difference in OS
months
courses, with
grade 3 to 4 non-
between groups; 3 year
bortezomib twice
hematologic AE were
OS approached 80% for
monthly as
significantly increased;
VMP and 85% for
maintenance (VMPT-
risks of cardiac toxicity
VMPT-VT
VT; n=254)
and TE and a non-
landmark analysis at the
significant increase in
end of 9 cycles showed a
infections with VMPT;
52% reduced risk of
decrease in any grade PN
progression for VMPT-
for VMP from 43% to
VT
21%, and reduction of
clinical benefit from the
grade 3 or 4 PN from 4%
4-drug combination is an
to 2% with change of
increasing CR rate with
twice- to once-weekly
maintenance prolonging
infusion of bortezomib;
response
AE during maintenance
median PFS for VMPT-
included PN in 6% of
VT was 37 months;
patients;
VMPT associated with
discontinuation for AEs
longer PFS in patients
was around 11%
younger than age 75
years; for patients older
than 75 years, there was
no difference in PFS
between treatments
Abstract
patients ASCT-
VDCR (standard
toxicities generally
CR = 5% to 12%, higher
621
eligible or not
bortezomib, 40 mg
similar across arms:
in the VDC-mod arm;
S. Kumar
eligible
dexamethasone,
nearly all patients had at
about half of patients
phase I/II
cyclophosphamide,
least 1 grade 3 AE;
with CR had MRD;
(NCT00507442)
and lenalidomide) vs.
2 on-study deaths in the
about half the patients in
phase I dose
VDR vs. VDC; VDC-
VDCR arm due to renal
each arm had a best
escalation of
mod (extra dose of
dysfunction
confirmed response of
cyclophosphamide cyclophosphamide to
about 15% grade 3 to 4
VGPR
and determine
improve response
PN
1 year estimated PFS =
regimen for phase
rate)
neutropenia higher with
85%
II
8 cycles of induction
cyclophosphamide-
estimated OS at 1 and 2
median F/U 18 to
and ASCT or 4 cycles
containing regimens;
years were 92% and
21 months
of maintenance
SC collected in nearly
76%, respectively for
a phase III trial
half of patients, and
VDCR, and 100% for
will compare
failure to collect occurred
VDC-mod
VDR and VDC-
in newly diagnosed
21

---

ASH 2010 for physicians
mod
patients
Abstract
transplant
MPR-R then
hematologic toxicities the
VGPR = 30% for MPR
622
ineligible, elderly
continuous
major AEs during
and MPR-R, 3 times
A. Palumbo
patients
lenalidomide at 10
induction
higher than with MP
phase III
mg per day as
grade 4 TE in 10% of
(60% reduced risk of
median F/U 25
maintenance vs. MPR
patients
progression overall, 69%
months
with no maintenance;
non-hematologic grade 3
for patients age 65 to 75
vs. MP with no
to 4 AE included 10%
years, 61% for patients
maintenance
infection and 2% to 5 %
over age 75 years)
pulmonary embolism
PFS = 31 months for
(PE) and DVT
MPR-R, 14 months for
AE during maintenance
MPR, and 13 months for
included a low rate of
MPT
cytopenias due to shorter
MPR-R associated with
follow-up and dose
longer PFS for patients
reductions to avoid
under the age of 75
discontinuation; low rate
years, with ISS stages I
of infection, some late
and II, and with lower
thrombosis
2M
discontinuation rate
69% reduced risk of
higher for patients over
progression after 9
the age of 75 years
cycles of MPR with
up to 3% solid tumors
lenalidomide
occurred (2% with MPR-
maintenance,
R), 2% AML, and less
significantly better than
than 1% MDS, but the
MPR without
risk of secondary tumors
maintenance
is higher with alkylating
no difference in OS
agents
among treatments; 1-
year survival about 92%,
2-year survival 75% to
82%
Relapsed/Refractory Myeloma
Sagar Lonial, MD, Hematology and Medical Oncology, Emory University, Winship Cancer
Institute, Atlanta, GA presented Relapsed Multiple Myeloma as part of the Multiple Myeloma
Education Program on Advances in the Basic Science of Plasma Cell Disorders, which he
chaired.
Dr. Lonial discussed new treatments and approaches for the management of relapsed disease. OS
and event-free survival (EFS) are poor in patients with disease resistant to bortezomib,
thalidomide, and lenalidomide. The options in the relapsed setting include existing novel agents,
existing older agents, and new agents in clinical trials. Early relapse should be treated with
combination therapy; later relapse with a single agent. If the previous myeloma was aggressive,
when it relapses it will require therapy sooner. Transplant-based salvage would be appropriate
for patients with DOR after their first transplant of 18 to 24 months. The second duration of
remission is usually shorter. It may offer a benefit for patients with pancytopenia that limits
further therapy on or off clinical trials. The goal of salvage transplant may be to restore
hematopoiesis to allow further chemotherapy treatment. Patients with aggressive, rapid, multiple
relapses require combination therapy, and therapy should not be delayed until symptomatic
22

---

ASH 2010 for physicians
relapse. Transplant-based therapy is short lived in this setting but offers quick disease control
and reconstitution of bone marrow, allowing patients to receive aggressive maintenance therapy
after. Ablative allogeneic transplant has a high transplant-related mortality (TRM), up to 40 to
50% within 1 year. Non-myeloablative transplant has a lower risk of TRM but equivalent
mortality at 2 years. Graft vs. host disease (GvHD) and relapse are issues beyond 2 years.
Dr. Lonial's talk ended with a summary of some of the new agents in development, including:
Pomalidomide, an IMiD structurally similar to thalidomide and lenalidomide, but
functionally different.
New proteasome inhibitors: carfilzomib, CEP 18770, NPR-0052
HDAC inhibitors, which target DNA methylation, including panobinostat, vorinostat, and
romidepsin, which may be synergistic with bortezomib. Panobinostat and vorinostat may
be synergistic with lenalidomide.
Agents that target the PI3K/Akt pathway and downstream targets include the Akt
inhibitor perifosine, which enhances bortezomib-induced cytotoxicity, and mTOR
inhibitors, which are also being tested in combination with bortezomib.
Monoclonal antibodies, including elotuzumab.
Dr. Lonial concluded that there is no easy algorhythm for treating relapsed myeloma. Patient-
specific issues, prior therapy, and FISH and cytogenetics should be considered and used to guide
treatment decisions.
Combination of Bendamustine, Lenalidomide, and Dexamethasone In Patients with
Refractory or Relapsed Multiple Myeloma Is Safe and Highly Effective: Results of a Phase
I Clinical Trial (Abstract 989) was presented by Suzanne Lentzsch, Department of Medicine,
Division of Hematology/Oncology, University of Pittsburgh School of Medicine and Cancer
Institute, Pittsburgh, PA
Objectives: The objectives of this study included determining MTD, safety, and the dose for a
phase II study of bendamustine, lenalidomide, and dexamethasone.
Doses: Bendamustine was given on days 1 and 2, lenalidomide on days 1 to 21, dexamethasone
on days 1, 8, 15, and 22 at 40 mg in 28-day cycles for a maximum of 8 cycles and 2 beyond the
best response. Doses of bendamustine and lenalidomide were escalated with a fixed dose of
dexamethasone for three dose levels.
Patients: Patients with relapsed or refractory myeloma who were not transplant eligible (N=25)
were included.
Side effects: There were no DLTs at level 1; at level 2 there was one instance of neutropenia, at
level 3 there were several. The MTD was 75 mg bendamustine, 10 mg lenalidomide. There were
no grade 4 non-hematologic events; grade 3 events included fatigue. Hematologic events
included cytopenias; grade 3 to 4 AE were mostly myelosuppression. Grade 1 PN occurred in
20%, grade 2 in 8%, with no grade 3 or 4 PN. All serious AE resolved (n=3). Patients received
aspirin and no TE were seen.
23

---

ASH 2010 for physicians
Results: The best responses after 2 or more cycles in 23 evaluable patients were ORR 66%,
clinical benefit response 91%, at least PR 66%. Median follow-up was 8.8 months. PD occurred
in 13 patients, and 4 died. Time to best response was 1.8 months, TTP was 4.3 months, time to
next therapy was 6.7 months, and the trial is still ongoing, with the last patient enrolled.
Treatment was tolerated in patients up to age 81 years (range 40 to 81 years), and was active in
heavily pretreated patients.
Diagnosis, Risk Stratification, and Staging
MGUS and SMM
Dr. Ola Landgren, MD, PhD, Medical Oncology Branch, National Cancer Institute, National
Institutes of Health, Bethesda, MD, presented MGUS and Smoldering Myeloma: New Insights
Into Pathophysiology and Epidemiology as part of the Multiple Myeloma Education
Program on Advances in the Basic Science of Plasma Cell Disorders, chaired by Sagar
Lonial, MD, Emory University School of Medicine, Atlanta, GA.
To answer the question whether myeloma is always preceded by MGUS, the National Institutes
of Health (NIH) conducted a prospective screening study for cancers, which identified 71
patients who developed multiple myeloma. In these patients, myeloma was always preceded by
MGUS. The FLC ratio was abnormal in many before the development of myeloma. The M-spike
significantly increased over time as the time of diagnosis of myeloma approached. Two patterns
were identified: half the patients had an evolving M-spike, and half had no M-spike. They are
currently looking at whether these populations are different. NIH/National Cancer Institute (NCI)
has an ongoing prospective natural history and molecular profiling study. All costs are covered
to get patients to the study site. The vast majority of patients with MGUS will never progress to
myeloma, so at this time there is no indication for screening for MGUS in the clinic. Patients
with SMM should be considered for clinical trials. Outside of clinical trials, observation is still
considered the standard of care. Better understanding of the pathogenesis from MGUS to
myeloma is needed. Dr. Landgren observed that there are 3 million people with MGUS in the US,
and only about 20,000 patients each year are diagnosed with myeloma. They are now screening
to identify patients with MGUS who didn't progress to myeloma. Patients with MGUS should be
made aware of the symptoms of transformation because they were the most likely to know when
transformation or progression is occurring.
Ultra-High Risk Myeloma
Hervé Avet-Loiseau, MD, PhD, University Hospital of Nantes, Nantes, France presented Ultra
high-risk multiple myeloma as part of the Education Program: Understanding and
Managing Ultra High-Risk Hematologic Malignancies chaired by Elihu J. Estey, MD,
University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA. The main
points of this presentation include the following:
An arbitrary definition of ultra high-risk myeloma is patients having a survival of 24
months regardless of their age. This is in contrast with median survival in the IFM trials
for those under age 65 years of almost 8 years and for older patients of somewhat over 4
years.
Extrinsic factors contributing to high-risk myeloma include 2M and lactate
24

---

ASH 2010 for physicians
dehydrogenase (LDH).
Intrinsic factors contributing to high-risk myeloma include plasma cell proliferation,
leukemic presentation, and certain genetic changes. Important chromosomal
abnormalities include t(4;14) and 17p deletion.
The ISS stage is also prognostic. For patients of any age, survival curves differ depending
on stage; those over age 65 years with ISS stage III have a median OS of less than 24
months, for those under age 65 years OS is probably about 28 months.
Several groups are identifying GEP profiles, SNPs, and chromosomal copy number
abnormalities that are associated with good or poor prognosis and that when combined
with 2M could be used to define the population with poor survival.
Plasma cell leukemia or leukemic presentations have a very poor prognosis but there are
no publications with a large number of patients with this condition.
High-risk myeloma can be defined currently as ISS stage III, presence of del 17p, poor
risk genomics by GEP or SNP array, or leukemic presentation.
Classical induction regimens such as VAD, TD, or bortezomib combinations are not
active, and Dr. Avet-Loiseau proposes treating with a rotation of combinations of active
drugs, including bortezomib, lenalidomide, dexamethasone, cyclophosphamide, and
possible doxorubicin for long-term treatment to reduce the aggressive myeloma clone.
HD Mel may be useful for patients under age 65 or 70 years, although the effective
number of courses is unknown. Bortezomib could be added; possibly VTD or VRD could
be used. Maintenance therapy for patients with high-risk myeloma is also an open
question; thalidomide may be deleterious, and little benefit has been shown for
bortezomib or lenalidomide.
There is an urgent need for a universal definition of ultra high-risk multiple myeloma and
a need for international trials in this patient group. Additionally, there is a need to
identify risk factors in phase III trials of agents such as carfilzomib, pomalidomide,
elotuzumab, and HDAC inhibitors, with the goal of identifying drugs for these high-risk
patients, who may constitute as much as 20% of the myeloma patient population.
Diagnosis, Prognosis, and Risk Assessment
IMF Symposium: Case Study 1: Diagnosis, Prognosis, and Risk Assessment in Multiple
Myeloma was presented by S. Vincent Rajkumar, MD, Mayo Clinic, Rochester, MN. Major
points of this presentation include the following:
Positron emission tomography (PET scan) can indicate myeloma disease that is not
otherwise apparent, and can determine if the spinal cord is compromised. For SMM and
solitary plasmacytomas, magnetic resonance imaging (MRI) of the entire spine can be
used to confirm the diagnosis and to determine the extent of disease when symptoms
don't agree with the skeletal survey. Lytic bone lesions are seen in 67% of patients at
presentation; the use of PET-CT (computed tomography) or MRI can detect more.
Current IMWG response criteria use FLC if patients lack measurable disease (M-spike).
FLC is also used for risk stratification of patients with MGUS, SMM, and solitary
plasmacytomas, and for screening in lieu of UPEP because it is easier to do a serum assay
25

---

ASH 2010 for physicians
than to collect a 24-hour urine sample.
A work-up of myeloma should consist of M-protein analysis using serum protein
electrophoresis (SPEP; detection rate is 82%) or serum immunofixation electrophoresis
(IFE; detection rate is 93%); if FLC or UPEP/UIFE is added, M-protein detection rises to
97-98%.
The Durie-Salmon staging system has stood the test of time and is still useful to
determine tumor burden. For the ISS a diagnosis of myeloma must be confirmed first;
then ISS can be used to stage the disease.
The role of GEP in risk stratification remains to be determined. 2M is a prognostic
factor because it is a surrogate for renal failure and high tumor burden, and a patient
presenting with renal failure needs the best available therapy early on.
Genetic Factors
Three studies assessing the role of genetic factors in myeloma are summarized in Table 8.
Clinical Outcome According to Both Cytogenetic Abnormalities (CA) Detected by
Fluorescence In Situ Hybridization (FISH) and Hyperdiploidy Assessed by Flow
Cytometry (FCM) In Elderly Newly Diagnosed Myeloma Patients Treated with A
Bortezomib-Based Combination, (Abstract 309) was presented by María Victoria Mateos,
University Hospital of Salamanca, Salamanca, Spain.
Prognostic Impact of Genetic Subgroups and Development of Gene Classifiers for
Response, PFS and OS In Multiple Myeloma Patients Treated with Bortezomib or
Conventional Agents In HOVON65/GMMG-HD4 Trial (Abstract 445) was presented by
Annemiek Broyl, MD, Department of Hematology, Erasmus MC, Rotterdam, Netherlands.
Bortezomib-Based Induction Treatments Improve Outcomes of Newly Diagnosed Multiple
Myeloma Patients with High-Risk Cytogenetic Abnormalities (Abstract 781) was presented
by Michele Cavo, Seràgnoli Institute of Hematology, Bologna University School of Medicine,
Bologna, Italy.
Table 8. Summary of Studies in Assessing Genetic Factors
Abstract
Patients
Genetic Analysis
Results
First Author
Phase
Follow-up
Agents and Doses
Abstract 309
patients age greater
Patient samples were
Response results recently published in
M.V. Mateos
than 65 years
analyzed by flow
Lancet Oncology.
(n=260)
cytometry for
Hypodiploidy is associated with poorer
(GEM05;)
ploidy. 232 patients
prognosis. DNA ploidy analysis found
induction therapy of
with FISH data: 188
hyperploidy in 132 (59%) of patients and
VMP vs. VTP for 6
were considered
non-hyperdiploidy (which included
cycles with weekly
standard risk by
hypodiploidy due to small numbers of
bortezomib, then
cytogenetics, 44
patients with this abnormality) in 92
26

---

ASH 2010 for physicians
each group split to
(19%) high risk,
patients. After induction therapy there were
maintenance with
with t(4;14) and del
no significant differences in efficacy and
either VT or VP
17 p; the high-risk
similar responses were seen after
group also had
maintenance; there were no differences seen
slightly higher 2M
between VT vs. VP maintenance. PFS from
and advanced stage
the first and second randomizations were
of disease
similar, but OS was significantly shorter in
the non-hyperdiploid patients; it was 63% at
3 years, and the difference was more
pronounced for VTP induction. With
bortezomib-based combinations, the RR and
CR rates are similar between high- and
standard-risk cytogenetics, but this does not
overcome the poor prognosis of high-risk
cytogenetics in terms of PFS and OS.
Abstract 445
HOVON-
clusters of patients
Bortezomib overcomes poor prognosis
A. Broyl
65/GMMG-HD 4
were defined based
associated with some clusters. Probes
(HD4) trial, n= 832
on translocations:
selected from HD4 were those most likely to
n = 570 bone
CD-1, CD-2, MS,
detect high risk patients. The HD4 high risk
marrow for plasma
and MF; 2
signature was validated in two independent
cell (PC)
hyperdiploid
data sets and identified a proportion of
purification, n = 341
clusters: HY and PR; patients with significantly lower survival
PC samples had a
a low bone sub-
irrespective of treatment and whether newly
purity of over 80%
cluster: LO; a
diagnosed or with relapsed disease. The
myeloid cluster; 2
predominant 1q and 1p aberrations in the
novel clusters CTA
UAMS set are not seen in the HD4 set, and
and PRL3. GEP was
there seems to be little or no overlap.
used to determine a
Patients with a higher hazard ratio were also
high risk signature.
found in the APEX trial data set, but more
The HD4 trial
work is needed for better prediction.
samples were used
as a training set.
Two independent
data sets were used
as external
validation: UAMS
patients on TT2
(n=351)and on TT3
(n=208)
Abstract 781
post-hoc analysis of
218 were transplant
Of the total 590 patient population, 261
M. Cavo
two GIMEMA trials
eligible and received
(44%) had no cytogenetic abnormalities; 175
of bortezomib-based
5 cycles of VTD
(30%) had del 13 q and 154 (26%) had
induction treatments
induction and
t(4;14) with or without del 17p. The high-
for newly diagnosed
consolidation after
risk population was subdivided in to those
patients, n=813;
ASCT. There were
with t(4;14) with or without del 13. The
after excluding 223
372 transplant-
three risk groups were evenly distributed
patients treated with
ineligible patients, of across the three treatments (VTD, VMP, and
TD, 590 patients
whom 181 received
VMPT). The high-risk group had a
received bortezomib;
VMP for 9 cycles
significantly higher frequency of higher ISS
bone marrow PC at
and 191 received
stage, and other demographic characteristics
diagnosis were
VMPT for 9 cycle
were generally same, age and 2M. When
isolated using
stratified by cytogenetic abnormalities, those
CD138-coated
with t(4;14) had shorter survival and lower
magnetic beads to
PFS than those with no cytogenetic
purity in excess of
abnormalities. Patients with both t(4;14) and
27

---

ASH 2010 for physicians
90%. For the
del 17p tended to have shorter PFS than
analysis, baseline
those with one abnormality, but survival for
data on del 13, t
those with either or both was about the same
4;14), and del 17 p
at 18 months. For patients with t(4;14) with
had to be available
and without del 17p, PFS was significantly
higher if they were treated with VTD vs.
TD. There was no difference in survival
between treatment with VMPT vs. VMP.
Bortezomib-based regimens were likely to
overcome poor prognosis related to several
high-risk cytogenetic abnormalities,
particularly t(4;14). There were only small
numbers of patients with del 17p, so the
difference in response was less clear, but
regimens containing combinations of three
or four drugs might help; however, this is
speculation.
Hevylite® Test
The Ratio of Monoclonal to Polyclonal Immunoglobulins Assessed with the Hevylite® Test
Predicts Prognosis, is Superior for Monitoring the Course of the Disease, and Allows
Detection of Monoclonal Immunoglobulin in Patients with Normal or Subnormal Involved
Immunoglobulin Isotype (Abstract 4038), was presented by Heinz Ludwig, Department of
Medicine, Wilhelminenspital, Vienna, Austria. The Hevylite® test was used to determine the
ratio of monoclonal to isotype-matched polyclonal immunoglobulins (heavy/light chain ratio;
HLC ratio) at baseline and to evaluate response in 133 patients with myeloma who had normal or
below normal levels of the involved immunoglobulin isotype. Conventional prognostic factors
were also measured, including IgG, IgA, 2M, FLC, LDH, and creatinine. Survival analysis and
Cox proportional hazards were performed. The HLC ratio is highly prognostic, improves
detection of variations in the course of the disease, and increases the diagnostic accuracy in
patients with normal or subnormal levels of the involved isotype, including those with negative
immunofixation (IFE). Note that The Binding Site, manufacturer of the Hevylite® test, is
awaiting a pre-IDE (Investigational Device Exemption) decision from the US FDA for
Hevylite® diagnosis and monitoring claims. Dr. Avet-Loiseau has looked at progression-free
survival (PFS) for 338 patients on IFM trials using traditional ISS classes based on 2M plus
albumin vs. 2M plus the Hevylite® ratio. ISS class results fall in 2 prognostic groups: ISS Stage
I, which has significantly longer PFS, vs. Stage II + III. The 2M plus Hevylite® ratio scoring
system showed a much lower p-value for separation of these two prognostic groups.
Conclusions
The trend of increased survival for patients with myeloma that began in the era of novel agents
(bortezomib, lenalidomide, and thalidomide) is continuing. The novel agents are now part of new
standards of care, with "novel-er" agents in development and early and late clinical trials, and
include targeted therapies. Future regimens are likely to be based on combination therapies with
unique mechanisms of action and non-overlapping toxicities. Risk stratification and tailoring of
therapy to individual patients' needs is advancing, and is including patient quality of life.
28

---